Pediatrics

Unconjugated hyperbilirubinemia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has neonatal unconjugated hyperbilirubinemia? What are the typical findings for this disease?

Postnatal unconjugated hyperbilirubinemia is a universal phenomenon when an infant’s total bilirubin (TB) level exceeds 17.1 μmol/L (1mg/dL), the upper range of normal value for adults. It manifests as jaundice (yellowness of skin) in about 80% of all newborns during the first week after birth. When the TB level is sufficiently elevated, bilirubin can appear in the mucous membranes, sclerae, and body fluids. Elevated unconjugated bilirubin accounts for most of the elevated TB and transcutaneous bilirubin (TcB) in the early neonatal period.

A progressive increase in TB during the first week after birth is usually benign and a function of an infant’s age in hours. An excessive rate of TB rise or TB levels >95th percentile for age in hours (as defined in the Bhutani nomogram) is considered significant and likely to require intervention. Excessive TB levels > 428 to 513 μmol/L (25 to 30 mg/dL) are associated with higher risk of bilirubin induced neurologic dysfunction (BIND) in infants >38 weeks of gestation.

What are the usual clinical manifestations?

Bilirubin deposition in the skin and subcutaneous tissues is responsible for the clinical signs of jaundice. The transport of bilirubin across the blood-brain barrier results in the clinical signs of BIND associated with TB levels that exceed the bilirubin-albumin binding capacity.

As a clinical sign, the “visual” presence of jaundice is not a reliable indicator of the TB level or its rate of rise of TB. However, detection of jaundice during the first 24 hours of birth is an index of severe hyperbilirubinemia and requires urgent attention. Thus, all newborn infants should be routinely monitored (every 6 to 8 hours) for development of jaundice in a well lit room.

Jaundice is detected by blanching the skin with digital pressure over the forehead, mid-sternum, iliac crest, patella, and ankles to reveal the underlying skin color. Jaundice usually appears on the nose/face and progresses caudally, but can sometimes fade in and appear as a tan. Color varies from lemony yellow to orange to sienna. Color may be masked and may be hard to detect in low ambient light, skin pigmentation, plethora, exposure to sunlight, or during phototherapy. Inability to detect jaundice or its absence is not indicative of the absence of hyperbilirubinemia.

How do you define the severity of postnatal hyperbilirubinemia

In 2004, the American Academy of Pediatrics recommended the infant’s TB level, rather than the unconjugated bilirubin fraction, as a guide to managing newborn jaundice.

The incidence and severity of neonatal hyperbilirubinemia varies by geography, institutions, racial and ethnic mix population, prevalence of hemolytic disorders, and breast feeding and birthing practices, as well as access to timely care.

TB levels have been traditional indicators of severity even though there are other useful and sensitive or specific predictors of BIND.

Table I lists the designation of severity, the reported incidence in the United States, and potential risks for hyperbilirubinemia in term infants managed in accordance with current practice.

Table I.

Adjective

TBlevel (mg/dL)

Percentile

Incidence

Occurrence

Risk of Kernicterus

Mild

<14

<40th

>60%

6 in 10

None reported

Significant

>17 to 20

>95th

8.1% to 10%

1 in 10

Unlikely

Severe

>20 to 25

>98th

1% to 2%

1 in >70

Cases reported

Extreme

>25 to 30

>99.9th

0.14% to 0.16%

1 in >700

Of concern

Hazardous

>30

>99.99th

0% to 0.032%

1 in >10,000

Unacceptable risk

The following features suggest severe hyperbilirubinemia:

1. Jaundice within the first 24 hours of birth (indicative of increased production, often due to hemolytic disease).

2. TB >95th percentile for age in hours, as plotted on the hour-specific bilirubin nomogram.

3. Rate of TB rise >0.2 mg/dL/hour (>3.5 μmol/L/hour).

4. Persistence of jaundice after 2 weeks of age in a term infant.

5. Conjugated bilirubin >1.0 mg/dL (17 μmol/L) if the TB is <5.0 mg/dL (86 μmol/L) or >10% to 20% of the TB if TB levels are >5.0 mg/dL (>86 μmol/L). These values are indicative of hemolysis.

What other disease/condition shares some of these signs?

Neonatal hyperbilirubinemia can be missed or not detected when observations are made in a poorly lit room or if the infant is not completely undressed to assess changes in skin tones in cephalo-caudal distribution.

Infants with darker skin (melanin) pigmentation, Hispanics or Asians with yellow chromophores, or infants of mixed ethnic backgrounds are considered most at risk for lack of recognition of jaundice. Thus, a low threshold should be used to measure TB.

Plethora, pallor, shock, or bruises may also confound the detection of jaundice.

The presence of jaundice does not distinguish unconjugated bilirubinemia from conjugated bilirubinemia (cholestasis). Thus, it is appropriate to measure fractionated TB, at least once, to exclude cholestasis.

What caused this disease to develop at this time?

Biologic risk factors:Bilirubin at low levels is a known potent anti-oxidant, and at high levels it is a silent neurotoxin.

Elevated unconjugated bilirubin levels may occur due to increased bilirubin production (degradation of heme moiety of hemoglobin) and/or diminished elimination (hepatic and intestinal) as well as the confounding unique neonatal phenomenon of entero-hepatic reabsorption of bilirubin. Bilirubin and carbon monoxide are equimolar degradation products of heme. The albumin-bound (non-water soluble) bilirubin that is unconjugated is processed in the hepatocyte to a water soluble glucoronidation by the enzyme uridine-di-phospho-glucuronosyl-transferase (UGT) and excreted in the gut. Some of this conjugated bilirubin is reconverted to unconjugated bilirubin by the enzyme β-glucuronidase and reabsorbed in the circulation (entero-hepatic recirculation).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Total Bilirubin: The most frequent test that measures unconjugated bilirubin is the total bilirubin (TB) in the blood. Four forms of bilirubin are present in the blood: unconjugated bilirubin, monoglucuronide, di-glucuronide, and delta bilirubin. Infants exposed to sunlight or phototherapy may also demonstrate photoisomers. Unconjugated bilirubin is insoluble in water.

Clinical laboratories usually measure bilirubin in the blood by “diazo reaction,” direct spectrophotometry, oxidative, enzymatic or chemical methods, and infrequently by high pressure liquid chromatography. Most analyzers that conform to current College of American Pathologists recommendations have been able to limit the total errors to ± 10% of reference method assay.

TcB values are not a substitute for the TB assay, but serve as valuable screening tools. They provide instant point of care results, are non-invasive, and spare the infant of painful heel sticks. Their use decreases the number of TB measurements. However, their accuracy is limited by ±2 mg/dL (34 μmol/L) of TB levels measured by diazo techniques, and TcB cannot be used for infants treated with phototherapy or directly exposed to sunlight.

Table IV lists other laboratory tests that are indicated as unconjugated hyperbilirubinemia progresses.

Would imaging studies be helpful? If so, which ones?

Imaging studies, such as magnetic resonance imaging, are only indicated in infants who were at risk for acute bilirubin encephalopathy, approached or needed an exchange transfusion, or manifested neurologic signs during or subsequent to extreme hyperbilirubinemia. These imaging studies are not indicated during the acute course of the illness, and their potential usefulness has not been validated for prognosis.

Radiographic and imaging studies for other clinical conditions that may be associated with severe hyperbilirubinemia are only indicated as deemed necessary for clinical diagnosis of primary conditions and would not usually guide management of hyperbilirubinemia. For example, enclosed hemorrhages such as subdural, subgaleal, hepatic, or those associated with fractures would necessitate specific diagnostic evaluation. Clinical management for bilirubin reduction would be determined by TB and the rate of TB rise. Similarly, gastrointestinal obstruction that promotes entero-hepatic circulation of bilirubin would need specific diagnostic radiographic evaluation.

Confirming the diagnosis

CLINICAL ALGORITHM TO MANAGE NEWBORN JAUNDICE

A clinical algorithm to prevent and treat unconjugated hyperbilirubinemia is based on a series of AAP recommendations and Agency for Healthcare Research and Quality (AHRQ) evidence reviews that are presented in Table V.

Table V.

PRIMARY PREVENTION

CLINICAL ACTION

LEVEL OF EVIDENCE

Breast feeding

Nurse 8-12/day

Quality C: benefit exceeds harm

Use of supplements

Routine use of water or dextrose is not indicated

Quality B/C: harm exceeds benefit

SECONDARY PREVENTION

Infant race and ethnicity as risk factors

East Asian and Mediterranean ethnicity are risk factors. African American race is at higher risk for G6PD deficiency

The evidence of quality for studies obtained over the past six decades has been summarized by 4 levels: A=Randomized controlled trials (RCT, most deemed unethical based on decades of practice); B=Overwhelming consistent evidence from observational studies or limited RCT; C=Multiple observational studies; D=Expert opinion.

Algorithm for follow-up (Table VI) and its timing is based on a recent expert opinion. These decisions are guided by the risk status of the TB/TcB plotted on the hour-specific bilirubin nomogram, gestational age and postnatal age (hours). Table VI outlines these recommendations.

If you are able to confirm that the patient has unconjugated hyperbilirubinemia, what treatment should be initiated?

PREVENTION AND TREATMENT OPTIONS

Prevention and treatment options include: a) serial clinical evaluation and assessment of TB/TcB, its rate of rise and decline as plotted on the hour-specific bilirubin nomogram; b) enteral nutritional support to increase milk transfer to the baby; c) use of effective phototherapy; d) rarely, a double volume exchange transfusion by an neonatal intensivist; and lastly e) in some infants and with consultation, the use of chemoprevention with intravenous immune globulin (IVIG) in certain immune-hemolytic disorders among infants at risk for exchange transfusion.

Effective phototherapy: A variety of devices are available to deliver effective phototherapy. These are not ultra-violet (UV) lights. Light sources are categorized as: a) light-emitting diodes (LED); b) fluorescent tubes with blue, special blue, or turquoise-green lights; c) metal-halide light bulbs; and d) high intensity LED devices. The ability to deliver effective phototherapy is outlined in Table VII.

The procedure is conducted in incremental steps to maintain isovolemia and stable hemodynamic well being. A team of experts to place central or peripheral catheters to optimally withdraw and replace equivalent volumes of blood can complete a double volume exchange transfusion within 2 hours of initiation. Traditionally, an umbilical venous catheter is placed for pull-push access. Most neonatologists prefer the use of arterial and venous catheters for the simultaneous and synchronized infusion and withdrawal method. Infants are continuously monitored for their hemodynamic and gas exchange status.

Follow-up monitoring of electrolytes, complete blood count, platelet count, and coagulation functions are key to recognizing early adverse signs.A crash-cart approach may need to be initiated in an infant with TB>25 mg/dL (427 μmol/L) or those with any neurologic signs.

Most patients with unconjugated hyperbilirubinemia respond to effective phototherapy. Prolonged use of phototherapy may be necessary among infants with inherited disorders of bilirubin metabolism. Identification of co-morbidities of hypothyroidism, galactosemia and Crigler-Najjar syndrome are likely to require specific interventions for the underlying condition.

What are the adverse effects associated with each treatment option?

Expectant observation: Serial bilirubin monitoring may increase the number of heel sticks in otherwise healthy newborns as the rate of TB rise is monitored; a combined use of TB/TcB may minimize the number of blood tests.

IIncrease enteral intake: Enteral intake of breast milk is a high priority for both family and healthcare provider. Interruption of breast feeding is seldom necessary. Preventive strategies to promote latching along with lactation counseling is associated with increased maternal milk production. Use of expressed maternal breast milk delivered through nipple feedings or other devices may be needed in late preterm infants with discoordinated nippling ability. Use of formula supplements should be rare and for minimal duration.

Phototherapy-related adverse effects are rare and usually not significant. Devices need to perform appropriately in environments of high humidity and oxygen as well as meet electrical and fire safety standards. Infants with known or suspected congenital porphyria or who have been prescribed photosensitizing drugs should not be exposed to phototherapy (particularly white light). Prolonged phototherapy has been associated with an increased risk of oxidant stress, lipid peroxidation, and riboflavin deficiency. Recent reports of malignant melanoma, DNA damage in skin, and skin changes have not yet been validated. Phototherapy does not exacerbate hemolysis. Bronzing of the skin may occur if the infant also has cholestasis.

Exchange transfusion-related adverse effects are serious and include mortality. A risk/benefit assessment for imminent mortality or lifelong irreversible neurologic morbidity is necessary in the context of the potential mortality of the procedure. The rarity of the need and use of this procedure has led to regional recommendations that this procedure be conducted at expert facilities. Timely triage, urgent referral, and emphasis on prevention of exchange transfusion are keys to safer newborn care.

What are the possible outcomes of neonatal unconjugated hyperbilirubinemia?

Benign outcome:Newborns with unconjugated hyperbilirubinemia who are managed expectantly and do not meet the AAP recommended thresholds for phototherapy are most likely to have benign outcomes. Those term infants in whom phototherapy is initiated in a timely manner and do not approach TB thresholds for exchange transfusion are also likely to have benign outcomes.

Subtle long-term effects of BIND have been suspected and debated, but are unproven in infants with diminished bilirubin-albumin binding capacity or prolonged significant hyperbilirubinemia, or in late preterm infants with significant hyperbilirubinemia.

Risks and Benefits. Parents should receive the FAQ (frequently asked questions) instruction sheet regarding newborn jaundice. These are available on the AAP and CDC websites in both English and Spanish. Parents should be reassured that with implementation of current AAP guidelines and post-discharge surveillance, infants will have a benign outcome. The risk of brain damage or need of exchange transfusion is usually preventable and rare with US guidelines. In the event an infant has an unusually acute and unpredictable course of unconjugated hyperbilirubinemia, the risks and benefits of interventions of individual procedures should be reviewed in the context of risks of lifelong irreversible post-icteric sequelae or kernicteric mortality.

How do these pathogens/genes/exposures cause the disease?

GENETIC BASIS OF PERSISTENT NEONATAL UNCONJUGATED HYPERBILIRUBINEMIA

Inherited non-hemolytic hyperbilirubinemic syndromes include: a) genetic glucuronidation defects that encompass Gilbert and Crigler-Najjar syndromes and b) defects of canalicular transport and hepatocellular storage such as Dubin-Johnson and Rotor syndromes. Arias syndrome is similar to Gilbert syndrome but reported as autosomal dominant with variable penetrance. The Lucey-Driscoll syndrome, a rare disorder, was attributed to a yet unidentified inhibitor of UGT from maternal breast milk.

Gilbert syndrome (also called Meulengracht syndrome) is characterized by mild, fluctuating non-hemolytic unconjugated hyperbilirubinemia that is not associated with hepatic inflammation. In the United States, about 9% of the population is homozygous and 42% is heterozygous for the Gilbert mutation.

In the neonatal population, neonatal hyperbilirubinemia is exacerbated with concurrent increased production or increased entero-hepatic recirculation. It is often a co-morbid condition with ABO incompatibility or G6PD deficiency. It is the most frequent basis for jaundice between ages 2-4 weeks, especially in breast-fed infants.

Gilbert syndrome is benign and confirmed by genotyping for polymorphisms of the UGT gene. Absence of the UG1TA1 enzyme is a drastic variant of the conjugation disorder (Crigler-Najjar type 1 disease) and is often fatal (unless treated with lifelong phototherapy) and is associated with mutations of exons 2, 3 and 4 of the UG1TA1 gene. Decreased conjugation ability to <30% of enzyme activity characterizes Crigler-Najjar type 2 disease associated with mutations in exon 1 of the UG1TA1 gene.

Gilbert syndrome probably represents a wider spectrum of UG1TA1 gene defects with the most severe form manifesting as Crigler-Najjar type 1 disease.

Other clinical manifestations that might help with diagnosis and management

CLINICAL MANIFESTATIONS OF BIND

Acute bilirubin encephalopathy presents as progressive changes in the infant’s mental, muscle tone, and crying status. Signs progress from drowsiness, poor feeding, and hypotonia that alternates with increased tone (dystonia), especially the extensor muscles. The latter progress to retrocollis and then to opisthotonos. Paralysis of upward gaze and mask-like kernicteric facies have been reported. Mortality is due to progressive coma or intractable seizures causing respiratory failure. The rate of progression of these signs depends on the rate of TB rise, duration of hyperbilirubinemia and associated co-morbidities.

Chronic bilirubin encephalopathy, or kernicterus, is an irreversible athetoid variety of cerebral palsy. It is characterized by generalized dystonia, paralysis of upward gaze, movement disorders, dental enamel of dysplasia of deciduous teeth, and varying severity of sensorineural hearing loss. Cognition is spared unless bilirubin encephalopathy is complicated by co-morbidities.

BIND refers to a wider spectrum of disorders that are confined to discrete neural pathways. For example, damage to auditory pathways may not result in sensorineural hearing loss, but might cause auditory neuropathy (dyssynchrony). More recently, visual-motor changes have been reported in moderately jaundiced infants.

What complications might you expect from the disease or treatment of the disease?

Extreme bilirubin neurotoxicity can be fatal, with necropsy signs of yellow staining of the basal ganglia. Cellular evidence of damage occurs in the basal ganglia, specifically, the globus pallidus and also observed in the sub-thalamus, central and peripheral auditory pathways, hippocampus, diencephalon, midbrain, pontine nuclei for respiratory, neuro-humoral and electrolyte control, brainstem nuclei for oculomotor and auditory function, and in the cerebellum (mostly vermis).

Infants at risk for diagnosis of G6PD deficiency or inherited persistent unconjugated hyperbilirubinemia may require further non-invasive testing such as G6PD genotype, UG1TA1 polymorphisms, and BSP and urine coproporphyrin assays. There are no indications for invasive diagnosis.

Infants at risk of adverse outcomes will need automated ABR, comprehensive ABR, and magnetic resonance imaging as a component of their follow-up during infancy and childhood.

How can neonatal unconjugated hyperbilirubinemia be prevented?

The primary and secondary prevention strategies listed above, implemented through a systems approach, has been shown to be the most effective process to prevent need for exchange transfusion, TB levels >30 mg/dL (513 μmol/L), and possibly kernicterus.

Ongoing controversies regarding etiology, diagnosis, treatment

In view of an established practice and access to reasonably safe and effective bilirubin reduction strategies that have evolved over the past seven decades, ongoing and currently unresolved controversies include:

#1. Does exchange transfusion prevent kernicterus in the absence of multiple RCTs?

#2. Does phototherapy prevent kernicterus in the absence of multiple RCTs?

#3. Does universal bilirubin screening prevent kernicterus in the absence of evidence for practices listed #1 and #2?

#4. Is the evidentiary ability of universal bilirubin screening to predict severe hyperbilirubinemia and need for phototherapy sufficient to implement mandatory pre-discharge screening?